Pyridones and process for making them



Patented Jan. 21, 1947 PYRIDONES AND PROCESS FOR MAKING THEM WilhelmWenner, Montclair, and John Thomas Plati, Passaic, N. J., assignors toHoffmann- La Roche Inc., Nutley, N. J., a corporation of New Jersey NoDrawing. Application July 17, 1945, Serial No. 605,624

13 Claims.

(IJHLOQR i H3 4 4 "a 3 and '5 a OH 6 o R.O.CH

NE NH wherein R is selected from the group consisting of hydrogen,alkyl, and aralkyl. Moreover, as is the case with pyridones, thecompounds may exist in the corresponding tautomeric hydroxy forms onion(3H3 u 1 n 0H:- --0H R.0.CH 0H N N wherein R. has the abovesignificance.

Specific examples of compounds which are embraced by the foregoingformulae are:

4ethoxymethyl-6-methyl-2-pyridone 4-benzyloxymethyl-6-methy1-2-pryidonel-methoxymethyl-6-methy1-2-pyridone 4-hydroxymethyl-6-methyl-2-pyridone4-methyl-6-ethoXymethyl-2-pyridone 4-methyl-6-methoxymethyl 2-pyridone4-methyl-6-hydroxymethyl-2-pyridone 4-methyl-6propyloxymethyl-2-pyridone4-methyl-6-benzyloxymethyl-2-pyridone It will, of course, be understoodthat while the compounds mentioned above are individual, pure compounds,it is contemplated that such may, if desired, be prepared andeffectively employed in the form of impure reacting mixtures. It willalso be appreciated that mixtures of two or more of said compounds, inthe pure or impure state, can also be utilized. 7

These novel Z-pyridones may be derived from 2 Z-pyridones in which the3-position of the nucleus is substituted "and which are represented bythe general formulae in which R has the above indicated meaning, and Zis carboxyl (COOH) or a functional derivative or equivalent thereof,such as cyano, carbamido, lactone, ester, salt, or anhydride. It will beapparent that in the case of an anhydride the actual formula wouldinvolve linkage of two pyridone nuclei, as is customary in anhydrides ofsuch organic acids. Accordingly, it will be understood that the formulaegiven above for the initial materials are intended to embrace theanhydrides. It will also be understood that the lactones will beembraced by the above formulae,'notwithstanding that such lactonespossess an inner ester linkage.

The anhydride structure of a suitable starting material may berepresented as follows:

([lH2.O.R onto R 00 0.0 c--' II CH3 0 0- ,o-m

NH M

The structure of a'lactone which may be employed is shown as follows:

The class of starting compounds includes, among others,3-cyano-4-ethoxymethyl-6-methyI-Z-pyridone, which is a well knownintermediate in the synthesis of vitamin B6 (see H. R. Rosenberg,Chemistry and Physiology of the Vitamins, 1942, pp. 204-5).3-cyano-4-methyl-6-ethoxymethyl-2-pyridone may also be employed. Thislatter material has, heretofore, been a waste product in the vitamin B6synthesis.

It will be obvious that the nature of the desired product will influencethe choice of the compound employed as a starting material. Thus thelactone of 3-carboxy-4-hydromethyl-6-methyl 2 Pyridone, having thefollowing formula yields 4 hydroxymethyl-fi-methyl 2 pyridone, havingthe formula CHaOH EXAMPLE 3 4-hydroxymethyZ-6-methyl-2-pyridone 10 partsof the lactone of 3-carbcxy-4-hydroxymethyl-6-methyl-2-pyridone and 100parts of It follows, additionally, that starting pyridones, I

substituted by methyl in the 6-position, will yield G-methyl substitutedend-products; while starting materials having an initial 4-methylsubstituent, will produce corresponding 4-methyl substitutedend-products.

The process, in general, involves subjecting the 3-substituted startingpyridone to the action of alkali, such as sodium hydroxide, potassiumhydroxide, sodium carbonate; and the like. The alkali agent has thesurprising ability of splitting off the substituent in the 3-position.The mechanism involves the conversion of cyano, carbamido, carbalkoxy,lactonized carboxylic derivatives, :and anhydrides, to the carboxylicacid in the form of its alkali salt. The latter then loses carbondioxide to yieldthe sought-for pyridones.

The reaction is carried out above 100 C.

The new compounds prepared by this method are crystalline solids, easilysoluble in organic solvents and somewhat soluble in water. They arestable; and, in most instances, they are capable of being distilled atreduced pressure withvout decomposition. They can be readily purified byrecrystallization. Being amphoteric in nature, they have the property offorming salts with both acids and bases, and thereby the solubility inwater is greatly increased. Halogenation of these compounds producesderivatives havingpharmaceutical value.

The procedure for the removal of the carboxyl group, or its functionalequivalent, comprises heating the initial Z-pyridone with dilute aqueousalkali to temperatures above 100C. for several hours. The rate ofreaction can'be increased by operating at high temperatures.Temperatures as high as 180 C. have been found to be suitable,

there being no decomposition of the reaction product even at this point.Preferably, a temperature of 160-180 C. is employed.

The full significance of the invention'will be made apparent by thefollowing examples, which are illustrative of the manner of producingsome of the compounds contemplated herein, and which will serve as aguide for those skilled in the art to produce other similar compounds.

. EXAMPLE '1 4-etho:cymethyZ-6-methyl-2-pyridone 5% aqueous sodiumhydroxide are heated in an.

EXAMPLE 4 4ethorcymethyl-G-methyl-Z-pyridone4-mcthyl-d-ethozcymethyZ-Z-pyridon A hot solution of 10 parts ofS-cyanoA-methyl G-ethoxymethyl-Z-pyridone in'100 parts of 4% sodiumhydroxide is heated in an autoclave to for 40 hours. The resultingmixture was cooled and saturated with carbon dioxide. 4- methyl-6'ethox'ymethyl-2 pyridone separates in colorless crystals of M. P. 104;7

. EXAMPLE 6 a 4-methyl-6-methokrymethyl2 pyridovze 10 parts of'3-cyanb-4-methyl-6-methoxymethyl-Z-pyridone are dissolved in 50 partsof 8% sodium hydroxide by heating to 809'. The hot solution is heated inan autoclave at180 for 15 hours. Hydrochloric acid is added to pH 7,.The solution is extracted repeatedly with chloroform. On distillation ofthe chloroform i-jmethyl-fimethoxymethyl-2epyridone is obtained,nw.hichupon recrystallization from ethyl acetateyields a product having a M. P.of 92. 7 7

EXAMPLE '7 -methyl-G-hydroscymethyl-2myridone A solution of 10 g. ofS-cyano--methyl-B- hydroxymethyl-Z-pyridone in 100 cc. of 5% so diumhydroxide is heated in an autoclave at for 24 hours. The solution, whichsmellsstrongly of ammonia, is acidified with hydrochloric. acid to a pHof 6. On standing crystals of 4 m'ethyl '6-hydroxymethyl-2-pyridonegradually appear- The filtrate is evaporated to dryness, and the residueis extracted with ethyl alcohol. (3n distillation of the alcohol afurther crop of l-methylfi-hydroxymethyl-Z-pyridone was obtained. The

. compound is purified by sublimation at 170 under a pressure of 0.2-0.4mm. and by crystallization from water or ethyl alcohol. The purecompound melts at 224=-22 l.5.

EXAMPLE 8 4-benzylozvymethyl-G-methyZ-Z-pyridone 5 parts of3-cyano-4-benzy1oxymethyl-6-methyl-2-pyridone, M. P. 210, and 20 partsof aqueous potassium hydroxide are heated in an autoclave to 160 for 20hours. The lightly colored solution is acidified with hydrochloric,acid, whereupon 4-benzloxymethyl-6-methyl-2-pyri done separates.Recrystallization from 70% alcohol yields the pure compound of M. P.138.

EXAMPLE 9 4-ethorymethyl-G-methyZ-Z-pyridone A mixture of 20 parts of3cyano-4=-ethoxymethyl-G-methyI-Z-pyridone, 10 parts of potassiumhydroxide, 100 parts of water and 100 parts of alcohol is heated in anautoclave at 170 for 24 hours. The solution is acidified withhydrochloric acid to pH 5.9 and distilled to dryness. The residue isextracted repeatedly with chloroform. The chloroform solution isdistilled to dryness, leaving almost pure 4-ethoxymethyl-6-methyl-2-pyridone, M. P. 108.

EXAMPLE 10 d-methorymethyl-6-methyZ-2-pyridone 6 parts of3-cyano-4-methoxymethy1-6-methyl- Z-pyridone, 4 parts of potassiumhydroxide, parts of methanol and 5 parts of water are heated to 160 forhours in an autoclave. The resulting solution is acidified withsulphuric acid to pH 6. It is then evaporated to dryness. The residue isextracted with chloroform. Evaporation of the chloroform gives4-methoxymethyl-6- methyI-Z-pyridone, M. P. 129.

EXAMPLE 1 1 ei-ethoryrrzethyZ-b'-methyZ-2-pyridone 20 parts of3-cyanoi-ethoxymethyl-6-methyl- Z-pyridone, 12.3 parts of sodiumcarbonate, and 200 parts of water are heated in an autoclave at 165-170for 24 hours. The mixture is acidified with hydrochloric acid to pH 1.6.and the undissolved material is filtered. The filtrate is treated withsodium hydroxide to pH 5.92 and extracted four times with 160 volumes ofchloroform. The chloroform is evaporated to give almost pure 4-ethoxymethyl-S-methyl-2-pyridone.

In place of the starting materials of the previous examples, thecorresponding 3-carboxy-2- pyridones or their esters, or their alkalimetal salts may be employed.

It will be appreciated that the proportions of reactants, times ofreaction, temperatures of reactions, and the like may be varied and thatsupplementary processes, such as purification and the like, may beresorted. to wherever found desirable or convenient. These and othervariations and modifications will be evident to those skilled in the artin the light of the guiding principles disclosed herein.

Wherever the term Z-pyridone is employed in the claims, it will heunderstood to cover both tautomeric forms, as specifically mentionedabove.

What We claim as new and desire to protect by,

Letters Patent of the United States is:

1. 2-pyridones selected from the group consisting of (fHaOJi $Hs I and lI CH3 0 R.O.CH2 O NH M wherein R is a member of the group consisting ofhydrogen, alkyl, and aralky 2. 2-pyridones corresponding to the formulaCH2.0.R

wherein R is a member of the group consisting of hydrogen, alkyl, andaralkyl.

Z-pyridones corresponding to the formula -z and l o 3.0. cm o NE NHwherein R is a. member of the group consistin of hydrogen, alkyl, andaralkyl, and Z is a member selected from the group of carlooxyl,carbamido, acyloxy, cyano, COO-alkali metal, and lactones and anhydridesthereof, with aqueous alkali at a temperature above C., for a. timesu'hicient to remove the Z substituent.

8. The process of claim 7, in which the temperature is maintained at-180 C.

9. The process of claim 7 wherein the material subjected to thetreatment with alkali is the 4- methyl substituted-Z-pyridone.

10. The process of claim 7 wherein the material subjected to thetreatment with alkali is the 6- methyl substituted-Z-pyridone.

11. The process of preparing e-ethoxymethyl- 5-methyl-2-pyridone, whichcomprises heating 3- cyano-4=-ethoxymethyl-G-methyl-fi-pyridlone with anaqueous solution of sodium hydroxide at C. for 24 hours.

12. The process for preparing 4-hydroxymethyl-G-methyl-Z-pyridone, whichcomprises heating the lactone of 4-hydroxymethyl-6-methyl-2-pyridone-3-carboxylic acid with dilute sodium hydroxide at C.for 10 hours.

13. The process for preparing 4-methyl-6- ethoxymethyl-Z-pyridone, whichcomprises heating 3-cyano-4-methyl-6-ethoxymethyl-2-pyridone with dilutesodium hydroxide at 165 C. for 40 hours.

WILHELM WENNER. JOHN THOMAS PLATI.

